(1) Field of the Invention
This invention relates to a novel peptide and to the use thereof for stimulating prolactin and growth hormone production.
(2) Discussion of Prior Art
Thymosin fraction 5 (TF-5) is a partially purified thymus gland preparation containing 40 to 60 peptides. TF-5 has been known to possess important immunopotentiating effects in animals and humans and can improve the physiology and function of the thymus gland. It has recently been demonstrated that TF-5 can also modulate neuroendocrine responses at the level of the pituitary gland and can, for example, stimulate production in vitro of prolactin (PRL) and Growth Hormone (GH) from anterior pituitary cells; see Spangelo, et al., Endocrinology, Vol. 121, No. 6, pp. 2035-2043 (1987).
The PRL and GH hormones are straight chain polypeptides produced in the anterior pituitary under the influence of corresponding releasing factors produced by the hypothalamus gland upon appropriate neural input. A primary biological activity of growth hormone (GH) (also known as somatotropin -STH) is the regulation of growth of body, organs and bones. GH also exerts a regulating action on the .alpha. cells of the pancreas for the production of the hormone glucagon which in turn acts on the liver to regulate the production of somatomedins. The primary biological activities of PRL that have been extensively studied and documented include the regulation of growth of the mammary gland, lactation and corpus luteum function Most recently it has also been observed that receptors for PRL are found on lymphocytes and that administration of PRL enhances immune responses (c.f. Spangelo, et al., Immunopharmocology, 14 (1987) pp. 11-20).
Growth in animals is believed to be regulated by a cascade of bio-regulatory molecules. Thus, the hypothalamus produces growth hormone releasing factor (GRF) and thyrotropin releasing hormone (TRH) which, in turn, act upon the pituitary to cause release of GH and PRL, respectively. Conversely, the pituitary is maintained under negative feedback by, for example, somatostatin (somatotropin release inhibiting factor - SRIF) and dopamine, to inhibit, respectively, secretion of GH or PRL.
Various clinical symptoms have been associated with deficiencies in the normal production of either of these hormones. For example, growth hormone production abnormalities may result in hypopituitary dwarfism and diabetes. Deficiencies or abnormalities in production of prolactin may result in deficient mammary gland development or inability to induce lactation. Other applications for human treatment by promoting growth hormone levels and/or prolactin include, for example, diffuse gastric bleeding, pseudoarthrosis, burn therapy, wound healing, dystrophy, bone knitting, osteoporosis, especially post-menopausal osteoporosis, and ovarian dysgenesis.
Deficiencies in production of growth hormone have been treated by administration of growth hormone derived from, for example, pituitary glands of human cadavers, or as a genetically engineered product. However, the former technique is inefficient, requiring a scarce source, while the latter is also expensive, and furthermore, yields only a single species of growth hormone, whereas, it has recently been disclosed that in the body a whole family of growth hormone compounds are normally secreted.
Various ways are known to stimulate release of growth hormone in vitro and in vivo. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus. Prostaglandin E.sub.1 and E.sub.2, theophylline, and certain cyclic nucleotides are believed to act directly on the pituitary to release growth hormone, however, their action is not believed to specifically release growth hormone nor are they believed to act at the growth-hormone-releasing hormone (GRF) receptors in the peripheral membrane and of the pituitary cell to initiate growth hormone release. Other potent GH releasing agents include galanin and epinephrine.
Another level of the regulation of pituitary hormone secretion is feedback control from target tissues, which may be negative or positive in nature. Among the many target tissues with feedback control of prolactin and GH secretion, the thymus has been shown to be one with a positive signal. For instance, neonatal thymectomy of the mouse results in severe degranulation of the acidophilic cells of the anterior pituitary, Bianchi, E., et al., 1971, J. Endocr., 51:1, and reduced serum levels of GH, Michael, S. D., et al., 1980, Biol. Reprod., 22:343. In addition, nude mice have smaller acidophilic cells, which are also degranulated, Ruitenberg, E. G., et al., 1977, J. Path., 121:225. Adult nude mice have reduced prolactin serum levels compared to normal littermates, Pierpaoli, W., et al., 1976, Clin. Exp. Immunol., 24:501. In the event that thymic tissue is implanted into these animals soon after birth, normal serum levels of prolactin will be found in adulthood, see Pierpaoli, id. In utero thymectomy of the Rhesus monkey also results in a 3-fold reduction of prolactin in the blood compared to surgical controls two days after birth, Healy, D. L., et al.. 1985, Biol. Reprod., 32:1127.
Other pituitary hormones may also be regulated by the thymus gland. Neonatal thymectomy of the mouse results in reductions of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, Michael, supra. LH and FSH are reduced in both the pituitary and the blood of the nude mouse, Rebar, R. W., et al., 1981, Endocrinology, 108:120 and Rebar, R. W., et al., 1982, Biol. Reprod., 27:1267. While both sexes had similar reductions in the gonadotropins, only the female nude mouse achieved complete normalization of pituitary hormone levels upon implantation with thymic tissue on the first day of life, Rebar, R. W., et al., 1980, Endocrinology, 107:2130. These hormonal changes may explain the ovarian dysgenesis and reduced ovarian weight often observed in the nude mouse, Ruitenberg, supra, and Shire, J. G. M., et al., 1974, Comp. Biochem, Physiol., 47A:93 and following neonatal thymectomy in normal rodents, Nishizuka, Y., et al., 1969, Science, 166:753.
GRF and analogs thereof have been isolated and synthesized by various techniques, including solid state peptide synthesis and genetic engineering; see, for example, U.S. Pat. Nos. 4,728,609, 4,734,399 and 4,732,972. There have also been proposed various synthetic peptides having pituitary growth hormone releasing activity; see, for example, U.S. Pat. Nos. 4,649,131, 4,622,312, 4,617,149, 4,411,890, 4,410,513 and many others.
Similarly, stimulation of PRL release from the pituitary has been proposed for various natural and synthetic chemicals, including, for example, the narcotic-analgesic morphine, the analgesic peptide methionine-enkephalin, analogs of methionine enkephalin, (-)-13.beta.-amino-5,6,7,8,9,10,11,12-octahydro-5.alpha.-methyl-5,11-metha nobenzocyclodecene-3-ol, thyrotropin releasing hormone (TRH), and other peptides, such as angiotension II (AII), and neurotensin (NT); see, for example. U.S. Pat. Nos. 4,061,737 and 4,150,147.
Both PRL and GH are anabolic hormones with regard to their metabolic actions on the thymus, spleen, lymph nodes and other components of the immune system. Abnormalities in pituitary function result in significant alterations in both immune and reproductive endocrine reactions that can be traced to reduced GH and/or PRL production.